Many currently used anti-leukemia drugs exert their effects by altering the structure of DNA. Characteristic forms of DNA damage result but quantitation of these DNA lesions has been limited by insensitive techniques. The recently developed, highly sensitive technique of DNA alkaline elution offers the opportunity to examine, at clinically relevant drug concentrations, the DNA damage and repair which follows treatment with certain anti-leukemic agents. Initially, two broad classes of drugs, bifunctional alkylating agents and intercalating compounds, will be investigated. The kinetics of formation and removal of DNA crosslinks following treatment of cells in culture with bifunctional alkylators will be correlated with effects on DNA synthesis and cell survival. The role of repair of DNA crosslinks in the biological resistance of certain cell lines to alkylating agents will be defined. An assay to predict the likelihood of clinical response to a given alkylating agent, based on DNA damage and repair, as measured by alkaline elution, will be tested. A unique DNA lesion, protein-concealed single strand breaks, has recently been described following treatment of cells with drugs which intercalate between base pairs of the nucleic acid. This lesion will be examined in depth to determine what part it may play in drug-induced inhibition of DNA and RNA synthesis and, ultimately, cell death. It is presumed that a clearer understanding of the action of antileukemic agents at the molecular level will enhance our ability to design more effective therapy.